2-h-pyrido(2,3-a)pyrazine derivatives and their acid-addition salts

ABSTRACT

The present invention provides new 2-azaquinolizidine derivatives and their acid-addition salts, which have neurotropic and antihistaminic effects and are valuable as medicaments, as well as a process for the production of these compounds.

United States atent [19] Kate [ Aug. 28, 1973 2-H-PYR1DO( 2,3-A)PYRAZINE DERIVATIVES AND THEIR ACID-ADDITION SALTS [75] Inventor: HideoKato, Motomachi, Japan [73] Assignee: Hokuriku Seiyaku Co., Ltd., Fukui,

Japan [22] Filed: Aug. 5, 1970 [21] Appl. No.: 61,422

[52] US. CL... 260/243 A, 260/268 TR, 260/268 R, 424/247, 424/250 [51]Int. Cl. C07d 51/72, C07d 94/13 [58] Field of Search 260/243, 268 BL,260/268 [56] References Cited UNlTED STATES PATENTS 2,902,485 9/1959Horclois 260/243 2,898,336 8/1959 Gailliot et al. 260/243 2,905,6689/1959 Jacob et al 2,979,502 4/1961 Gailliot et a1. 260/243 OTHERPUBLICATIONS Freed et al., J. Org. Chem., Vol.25, p. 2108-21 13, 19-60).

Primary Examiner-Harry I. Moatz Attorney-Milton J. Wayne 5 7] ABSTRACT 9Claims, No Drawings 2-I-I-PYRIDO(2,3-A)PYRAZINE DERIVATIVES AND THEIRACID-ADDITION SALTS DETAILED EXPLANATION OF INVENTION The presentinvention relates to new 2- 5 azaquinolizidine derivatives of thegeneral formula wherein X represents hydrogen atom, a halogen atom, ahalogenomethyl group or methoxy group, Z represents sulfur atom or aradical CI-I CH or CI-I CH and n is an integer of l 5, and theiracidaddition salts, as well as a process for the production of thesecompounds.

The 2-azaquinolizidine derivatives and their acidaddition salts are allnew substances which have never been described in the literature. Thesecompounds have antihistaminic effects and accordingly are valuable asmedicaments.

The process of this invention is represented by the following equation:

-cmcn wherein X, Z and n have the same meanings as above, and Xrepresents a halogen atom.

Namely, the process comprises the following three steps:

1. the step of reacting l-(B-chloroethyU-Z- chloromethylpiperidine ofthe formula (I) with a hydroxy-alkylamine of the general formula (II) toform a 2hydroxyalkyl2-azaquinolizidine of the general formula (III),

2. the step of halogenating a 2-hydroxyalkyl-2- azaquinolizidine of thegeneral formula (III) in its hydroxyl group to form a 2-halogenoalkyl-2-azaquinolizidine of the general formula (IV), and

3. the step of condensing a 2-halogenoalkyl-2- azaquinolizidine of thegeneral formula (IV) with a phenothiazine derivative or a5I-I-dibenzo(b,f-azepine derivative of the general formula (V) to form a2- azaquinolizidine derivative of the general formula (VI).

In the step l l-(B-chloroethyl )-2- chloromethylpiperidine is reactedwith for example monoethanolamine or 3-amino-l-propanol in the presenceof a de-hydrogen halogenide agent such as potassium carbonate, sodiumacetate, pyridine or a tertiary amine. The reaction may be carried outwithout any solvent or in a solvent, for example, in an organic solventsuch as acetone, chloroform, benzene, toluene,

etc.

In the step (2), Z-(B-hydroxyethyD-Z- azaquinolizidine orZ-(y-hydroxypropyU-Z- azaquinolizidine so obtained is halogenated in aconventional manner, using a halogenating agent such as thionylchloride, etc. This reaction too may be carried out without any solventor in a solvent such as chlorofonn, dichloromethane, etc.

In the step (3), the resulting halogenated compound, i.e. a2-halogenoalkyl-2-azaquinolizidine is condensed with a phenothiazinederivative or a 5I-I-dibenzo(b,f)- azepine derivative of the generalformula (V) in an organic solvent such as benzene, toluene, xylene, etc.in the presence of a condensing agent such as sodium arnide, sodiumhydride, metallic sodium or the like. The condensation reaction issuitably carried out at room temperature or at the boiling point of thesolvent used.

Compounds of the above general formula (VI) can be converted into theirsalts according to a conventional method. As acids suitable for the saltformation, there can be mentioned inorganic and organic acids whichyield pharmaceutically acceptable salts, such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, lacticacid, salicylic acid, benzoic acid, tartaric acid, maleic acid, gallicacid, methanesulfonic acid, etc.

The invention is further illustrated by the following examples:

the

EXAMPLE 1 2-( y -hydroxypropyl)-2-azaquinolizidine and its hydrochloride20.8 grams of l-(B-chloroethyl)-2- chloromethylpiperidine and 21.5g oftriethylamine are dissolved in lOOml of chlorofonn. To the solutionobtained, a solution of 8.7g of 3-amino-l-propanol in ml of chloroformis added dropwise. The mixture is refluxed for 18 hours and thenconcentrated under reduced pressure. The resulting residue is madealkaline with an aqueous sodium hydroxide solution, and the baseprecipitated is extracted with chloroform. The

chloroform extract is dried over anhydrous sodium suifate and, afterdistilling off the chloroform, distilled under vacuum to give a basiccompound having a boiling point of 125 128C/2mmHg.

The base is dissolved in anhydrous ethanol and made acidic withethanolic hydrogen chloride. The crystals precipitated are separated byfiltration and recrystallized from anhydrous ethanol, whereby purecrystals having a melting point of 232 236C are obtained.

Analysis for C H N OCl Calculated: C, 48.71; H, 8.93; N, 10.33

Found C, 48.69; H, 9.07; N, 10.12

EXAMPLE 2 Z-(B-hydroxyethyl)-2-azaquinolizidine To the solution obtainedby dissolving 12.8g of l-(B- chloroethyl)-2-chlorornethylpiperidine and13.2g of triethylamine in 80ml of chloroform, a solution of 4.4g ofmonoethanolamine in 40ml of chloroform is added dropwise. The mixture isrefluxed for 18 hours and then treated in the same manner as in Example1, whereby Z-(B-hydroxyethyl)2-azaquinolizidine having a boiling pointof 100 103C/2mmHg is obtained.

EXAMPLE 3 2-( y -chloropropyl)-2-azaquinolizidine Eight grams of 2-( 'y-hydroxypropyl)-2- azaquinolizidine obtained in Example 1 are dissolvedin 100ml of dichloromethane. To the resulting solution, a solution of17g of thionyl chloride in 80ml of dichloromethane is added dropwise.The mixture is refluxed for 3 hours and then evaporated under reducedpressure. The residue is dissolved in ice-water and made alkaline withan aqueous sodium hydroxide solution. The base precipitated is taken inether and the ether extract is dried, distilled off the ether, anddistilled under vacuum to give 2-( -chloropropyl)-2-azaquinolizidinehaving a boiling point of 129 133C/5mmHg. The hydrochloride has amelting point of 235 237C.

Analysis for C l'l N cl Calculated: C, 45.60; H, 8.00; N, 9.67

Found C, 44.89; H, 8.12; N, 9.60

EXAMPLE 4 2-( B -chloroethyl)-2-azaquinolizidine 4 grams of 2-( B-hydroxyethyl)2-azaquinolizidine obtained in Example 2 are dissolved in50ml of dichloromethane. To the resulting solution, a solution of 9g ofthionyl chloride in 40ml of dichloromethane is added dropwise. Themixture is refluxed for 3 hours and then a small amount of water isadded thereto dropwise. The whole is made alkaline by adding an aqueoussodium hydroxide solution dropwise, and then the base is taken indichloromethane. The dichloromethane extract is dried, distilled off thedichloromethane, and distilled under vacuum to give 2-( B-chloroethyl)-2-azaquinolizidine having a boiling point of 99101C/3mmHg.

EXAMPLE 10-[ 'yl 2-( 2-azaquinolizidyl -propyl ]-phenothiazine To asuspension of 2.8g of phenothiazine in 25ml of xylene, 0.6g of sodiumamide is added and the mixture is refluxed for 3 hours. After additionof a solution of 3.4g of 2-(-y-chloropropyl)-2-azaquinolizidine obtainedin Example 3 in ml of xylene, the whole is further refluxed for 5 hoursand thereafter extracted with 1.5N-

hydrochloric acid. The aqueous layer is washed with ether and madealkaline with sodium hydroxide. The base precipitated is taken in ether.The ether solution is dried, distilled off the ether, and distilledunder vacuum to give IO-[y- {2-(2-azaquinolizidyl)} -propyl]-phenothiazine having a boiling point of 230 235C/l.5mm1-lg. Thehydrochloride has a melting point of 196C.

Analysis for c,,i-i,,N,sci,

Calculated: C, 61.02; H, 6.85; N, 9.31

Found: C, 60.83; H, 7.12; N, 9.26

EXAMPLE 6 10-[5- {2-(2-azaquinolizidyl)} -ethyl]-phenothiazine 0.64 gramof sodium amide is added to a suspension of 2.9g of phenothiazine in25ml of xylene, and the mixture is refluxed for 3 hours. Then a solutionin 15ml of xylene of 3.3g of Z-(B-chloroethyD-Z- azaquinolizidineobtained in Example 4 is added dropwise, and the whole is furtherrefluxed for 5 hours, washed with water, and extracted with 1.5N-hydrochloric acid. The acidic extract is made alkaline with sodiumhydroxide. The base so precipitated is taken in ether, and the ethersolution is dried, distilled off @eether, distilled under vacuum to giveIO-[B- {2(2-azaquinoliz id yl) ethyl] -phenothiazine having a boilingpoint of 225 227C/1.3mmHg. The hydrobromide has a melting point of 189191.5C, and the picrate a medt mg pair of 236239C Calculated: C, 49.57;H, 4.04; N, 15.30

Found: C, 49.21; H, 4.15; N, 15.04

EXAMPLE 7 10-[7- 2-(2-azaquinolizidyl -propyi]-2-chlorophenothiazine1.35 grams of sodium amide are added to a suspension of 7.3g of2-chlorophenothiazine in 60ml of xylene, and the mixture is refluxed for3 hours. After a solution in 30ml of xylene of 7.5g of2-(-y-chloropropyl)- 2-azaquinoli zidine obtained in Example 3 is addeddropwise, the whole is further refluxed for 5 hours and then washed withwater and extracted with 1.5N- hydrochloric acid. The acidic extract ismade alkaline with sodium hydroxide and the base precipitated is takenin ether. The ether solution is dried, distilled off the ether,distilled under vacuum to give IO-[y- {2:(2-azaquinolizidyl) WW{-propyl]2-chlorophenothiazine having a boilingpoint of 234236C/l.5mmHg. The hydrochloride has a melting point of 195 197C.

Analysis for c n mscl,

Calculated: C, 56.73; H, 6.21; N, 8.63

Found: C, 56.41; H, 6.50; N, 8.35

EXAMPLE 8 lO-[B- {2-(2-azaquinolizidyl)} -ethyll-2-chlorophenothiazine0.44 gram of sodium amide is added to a suspension in 30ml of toluene of2.38g of 2-chlorophenothiazine, and the mixture is refluxed for 3 hours.After a solution in 20ml of toluene of 2.3g of Z-(B-chloroethyH-Z-azaquinolizidine obtained in Example 4 is added dropwise, the whole isfurther refluxed for 5 hours and then washed with water and extractedwith 1.5N- hydrochloric acid. The acidic extract is made alkaline withsodium hydroxide, and the base precipitated is taken in ether. The ethersolution is dried, distilled off the ether, and distille d urgle vacuumto give lO-[ B- {2-(2-azaquinoliz idyD} -ethyl] -2-chlorophen0thiazinehaving a boiling point of 225 228C/1.4mmHg. The picrate has ameltingpoint of 235 236.2C. Analysis for C l-l N SCl-2(NO C H OHCalculated: C, 47.58; H, 3.76; N, 14.69 Found: C, 47.43; H, 3.89; N,14.37

EXAMPLE 9 S-[B- {2-2-azaquinolizidyl)} ethyl]-10.11 dihy dro-5 I-ldiBenzo-(bflazepine and its hydrochloride 0.25 gram of sodium amide and1.25g of 10,1ldihydr-5H-dibenzo-(b,f)-azepine are added to 20ml ofanhydrous xylene and the mixture is refluxed for 3 hours. After asolution of 1.3g of Z-(B-chloroethyD-Z- azaquinolizidine in 10ml ofanhydrous xylene is added dropwise, the whole is further refluxed for 7hours and, after cooling, extracted with 1.5N-hydrochloric acid. Theaqueous layer is made alkaline with sodium hydroxide, and the base istaken in ether. The ether layer is washed with water, dried, distilledoff the ether, and distilled under vacuum to give the final product.

The base thus obtained is dissolved in anhydrous ether and acidifiedwith ethereal hydrogen chloride. The crystals precipitated are separatedby filtration and recrystallized from anhydrous ethanol, whereby purehydrochloride having a melting point of 204.5 206C is obtained.

Analysis for C H N -2HCl'H O Calculated: C, 63.71; H, 7.80; N, 9.29

Found: C, 63.97; H, 7.87; N, 8.93

EXAMPLE l0 -['y- {2-(2-azaquinolizidyl)} -propyl] 4 1 0,1 1-diliydro-5Hdibenzo-(b,fiizaine and its hydrochloride 0.26 gram of sodium amide and1.3g of 10,11- dihydro-5l-l-dibenzo-(b,f)-azepine are added to 20ml ofanhydrous xylene, and the mixture is refluxed for 3 hours. After asolution in ml of anhydrous xylene of 1.45g ofZ-(ychloropropyl)-2-azaquinolizidine is added dropwise, the whole isrefluxed for further 7 hours. By the same after-treatment as in Example9, the aimed base is obtained from the reaction mixture. The base isdissolved in anhydrous ether and acidified with ethereal hydrogenchloride. The crystals precipitated are separated by filtration andrecrystallized from anhydrous ethanol whereby pure crystals having amelting point of 212 213.8C are obtained.

Analysis for C H N -2HClH O Calculated: C, 64.37; H, 7.99; N, 9.01

Found: C, 64.12; H, 8.16; N, 9.07

EXAMPLE I 1 S-[B- 2-(2-azaquinolizidyl)}-ethyl]-5H-dibenzo-(b,f)-azepine and its hydrobromide 0.59 gram ofsodium amide and 2.9g of SH-dibenzo- (b,f)-azepine are added to 50ml ofanhydrous xylene, and the mixture is refluxed for 3 hours. After asolution in 25ml of anhydrous xylene of 3g of 2-(B-chloroethyl)-2-azaquinolizidine is added dropwise, the whole is refluxed for further7 hours. After the same aftertreatment as in Example 9, the final baseis obtained.

The base is dissolved in anhydrous ether and acidified with etherealhydrogen bromide. The crystals precipitated are separated by filtrationand recrystallized from anhydrous ethanol whereby pure crystals having amelting point of 221 223C are obtained.

Analysis for C H N -2HBrH O Calculated: C, 53.45; H, 6.17; N, 7.79

Found: C, 53.31; H, 6.35; N, 7.80

What is claimed is:

l. A compound of the formula wherein X is a member selected from thegroup consisting of a hydrogen atom, and a halogen atom, Z is a memberselected from the group consisting of a sulfur atom, a -CH CH group anda CH CH group and n is an integer of l to 5 and the pharmaceuticallyacceptable acid addition salts thereof.

2. A compound according to claim 1 wherein n is an integer of 2 or 3 3.A compound according to claim 1 which is lO-[y- 2-{(2H-pyrido(2,3-a)pyrazine} -propyl]-phenothiazine and pharmaceuticallyacceptable acid addition salts thereof.

4. A compound according to claim 1 which is l0[B- {2-(2H-pyrido(2,3-a)pyrazine} -ethyl]-phenothiazine and pharmaceuticallyacceptable acid addition salts thereof.

5. A compound according to claim 1 which is lO-[y- {2-(2 H-p'yfidoQ ,3a)pyrazine} propyl I 2- chlorophenothiazine and pharmaceuticallyacceptable acid addition salts thereof.

6. A compound according to claim 1 which is IO-[B- {2-ff-l-pyfidofigaipyrazine} -ethyl]-2-chlorophenothiazine and pharmaceuticallyacceptable acid addition salts thereof.

7. A compou nd according to claim 1 which is 5-[B-{2-(2H-pyrido(2,3-a)pyrazine} -ethyl l 0, lldihydro-5H-dibenzo-(b,f)-azepine and pharmaceutically acceptable acidaddition salts thereof.

8. A compound according to claim 1 which is S-[y- -propyl]-10, l1-dihydro-SH-d-ibenzo-(b,f)-azepine and pharmaceutically acceptable acidaddition salts thereof.

9. A compound according to claim 1 which is S-[B-2-(2H-pyrido(2,3-a)pyrazine} -ethyl]3fl dibeniolbfiazepine andpharmaceutically acceptable acid addition salts thereof.

2. A compound according to claim 1 wherein n is an integer of 2 or 3 3.A compound according to claim 1 which is 10-( gamma-2-((2H-pyrido(2,3-a)pyrazine)-propyl)-phenothiazine andpharmaceutically acceptable acid addition salts thereof.
 4. A compoundaccording to claim 1 which is 10( Beta - gamma2-(2H-pyrido(2,3-a)pyrazine)-ethyl)-phenothiazine and pharmaceuticallyacceptable acid addition salts thereof.
 5. A compound according to claim1 which is 10-( gamma -(2-(2H-pyrido(2,3-a)pyrazine-propyl)-2-chlorophenothiazine and pharmaceutically acceptable acid additionsalts thereof.
 6. A compound according to claim 1 which is 10-( Beta-(2-(2H-pyrido(2,3-a)pyrazine)-ethyl)-2-chlorophenothiazine andpharmaceutically acceptable acid addition salts thereof.
 7. A compoundaccording to claim 1 which is 5-( Beta -(2-(2H-pyrido(2,3-a)pyrazine)-ethyl)-10, 11-dihydro-5H-dibenzo-(b,f)-azepine and pharmaceuticallyacceptable acid addition salts thereof.
 8. A compound according to claim1 which is 5-( gamma - (2-(2H-pyrido(2,3-a)pyrazine)-propyl)-10,11-dihydro-5H-dibenzo-(b,f)-azepine and pharmaceutically acceptable acidaddition salts thereof.
 9. A compound according to claim 1 which is 5-(Beta - (2-(2H-pyrido(2,3-a)pyrazine)-ethyl)-5H-dibenzo-(b,f)-azepine andpharmaceutically acceptable acid addition salts thereof.